Beta Blockers and Calcium Channel Antagonists

GENERAL PRINCIPLES

Beta-adrenergic antagonists (beta blockers, BBs) and calcium channel antagonists (CCAs) are widely prescribed for hypertension, atrial fibrillation and other dysrhythmias, and noncardiac indications such as essential tremor, migraine prophylaxis, Raynaud's, and situational anxiety.

Pathophysiology

• BBs antagonize beta-adrenergic receptors in the myocardium and pacemaker system, producing decreased chronotropy and inotropy.

î Sotalol has BB activity and is also an IKr antagonist (class III antidysrhythmic). In overdose, it produces QT prolongation and bradycardia, which creates a high risk for torsades de pointes.

î Propranolol has cardiac sodium channel antagonist properties in overdose and is also lipophilic enough to cross the blood-brain barrier and produce mental status changes and seizures in overdose.

• CCAs inhibit the entry of calcium into cells.

î The non-dihydropyridine CCAs (diltiazem, verapamil) act primarily on cardiac myocytes and cells of the pacemaker system, producing decreased chronotropy and inotropy.

î The dihydropyridine CCAs (amlodipine, nifedipine) act primarily on peripheral vascular smooth muscle, producing vasodilation.

î In significant overdose, all CCAs lose channel selectivity and can affect all types of calcium channels.

DIAGNOSIS

Clinical Presentation

• The cardinal features of BB and CCA poisoning are hypotension and bradycardia.

In certain cases of CCA poisoning in which vasodilation predominates, patients may initially present with a normal heart rate or tachycardia.

• Mental status will typically be normal (even with profound shock) until late in the course of poisoning. This is not always true in the case of poisoning by propranolol, which is centrally active and may cause mental status changes or seizures.

Differential Diagnosis

Consider other conditions that may cause hypotension and bradycardia: digoxin/cardioactive steroid poisoning, sympatholytic poisoning, myxedema coma, hypothermia, high-grade heart block with cardiogenic shock, and shock with profound acidosis or hyperkalemia.

Diagnostic Testing

LABORATORIES

• Blood glucose may help distinguish BB from CCA poisoning: CCA poisoning tends to present with hyperglycemia, while BB poisoning typically presents with euglycemia or hypoglycemia.

• Obtain a BMP to assess for renal function and potassium, which have implications for the monitoring of some treatments for BB and CCA poisoning.

ELECTROCARDIOGRAPHY

• All BBs and CCAs may produce sinus bradycardia and AV blocks.

• Sotalol will prolong the QT interval.

• Propranolol may prolong the QRS interval in overdose.

TREATMENT

• Mild poisoning may respond to intravenous fluids and calcium. If calcium is used as a primary treatment in moderate or severe cases, high doses may be required.

• BB poisoning, especially in mild cases, may respond to glucagon.

î Large amounts of glucagon (typically 5-10 mg IV in an average adult patient) are required.

î The duration of action of glucagon is very short. Patients responding to glucagon boluses should be started on a glucagon infusion (dosed at the effective bolus dose per hour, and titrated to effect).

î Many hospitals do not stock enough glucagon for this indication.

î Significant GI upset should be anticipated.

• Patients with significant toxicity should be treated with vasopressors and/or high-dose insulin.

î Vasopressors may be more effective in patients with a predominantly vasodilatory phenotype (preserved ejection fraction, near-normal heart rate, profound systemic vasodilation).

#9632; Norepinephrine and vasopressin are reasonable first-line agents; epinephrine, phenylephrine, and dopamine may also be added.

#9632; Multiple agents at very high doses may be necessary.

î High-dose insulin (also known as hyperinsulinemic-euglycemic therapy, HIET) may be more effective in patients with poor inotropy and chronotropy. ²¹

#9632; The initiation dose of HIET is a bolus of 1 unit/kg regular human insulin IV, followed by an infusion of 1-10 unit/kg/h.

#9632; Aggressive dextrose supplementation and very frequent blood glucose checks are mandatory to avoid iatrogenic harm. Potassium should also be monitored closely. Patients with CCB poisoning may have profound insulin resistance and require little or no supplemental dextrose (frequent glucose checks still necessary).

î In many cases, the combination of vasopressors and HIET is reasonable and effective.

• Methylene blue infusion (1-2 mg/kg/h) may reverse peripheral vasoplegia.

î Many hospitals do not stock enough methylene blue for this indication.

• Intravenous lipid emulsion (1.5 cc/kg bolus, max 100 cc, followed by infusion of 0.25 cc/kg/min for 20 minutes) may be considered for patients refractory to the above therapies.

• VA ECMO is effective and lifesaving in severe poisoning, although not without risks.

î Have a low threshold to transfer patients with significant poisoning to an ECMO-capable center.

• Hemodialysis may be used to enhance the elimination of select BBs only: nadolol, acebutolol, sotalol, and atenolol. It otherwise has no role.

• Atropine and electrical pacing are unlikely to be effective in significant poisoning.